The canonical Wnt/β-catenin pathway is of particular importance in regulating cell proliferation, differentiation, and cell-cell communication. The aberrant activation of Wnt/β-catenin signaling leads to the initiation and progression of many cancers such as colorectal cancers, leukemia, and multiple myeloma. Moreover, Cancer stem cells, which are resistant to conventional chemo- and radiotherapies and especially virulent, are also controlled by the hyperactivation of canonical Wnt signaling. The formation of the β-catenin/Tcf complex in the cell nucleus is the penultimate step of canonical Wnt signaling. The overactivation of canonical Wnt signaling correlates with the formation of this complex. Selective inhibition of the β-catenin/Tcf protein-protein interaction (PPI) represents an appealing therapeutic strategy.
Despite advances in research directed to identifying inhibitors the Wnt signaling pathway generally, and specifically inhibitors of β-catenin/Tcf PPIs, there remains a scarcity of compounds that are both potent, efficacious, and selective inhibitors of β-catenin/Tcf PPIs and also effective in the treatment of cancers and other diseases associated with uncontrolled cellular proliferation, e.g., cancers and fibrotic diseases. These needs and other needs are satisfied by the present invention.